The present invention relates to surface modification of metal supports, including medical devices, to specifically and efficiently introduce biologically active molecules and macromolecules into mammalian cells. Of particular interest is a delivery system for nucleic acid without the use of surface coatings, thereby enhancing biocompatibility.
Many types of metal supports, such as stainless steel and titanium medical devices have mechanical properties that are advantageous, but are generally incompatible with blood or tissue. To this end, polymer coatings for metal supports have been developed in the anticipation of improving biocompatibility and minimizing the battery of adverse cellular responses associated with foreign materials.
Surface coatings and treatments, however, are problematic in that they can invoke acute or chronic inflammatory responses due to the coatings themselves. The use of synthetic polymers and biopolymer coatings for delivery purposes can, in some instances, also result in an undesirable hyper-proliferation response among cells that contact the polymeric material. Polyurethane, poly(dimethyl siloxane) and polyethylene terephthalate coated stents cause inflammation and thrombus formation. Low molecular weight poly-L-lactic acid coating also causes an inflammatory response. Lincoff et al., J. Am. Coll. Cardiol., 29, 808.16 (1997). Polymer coated medical devices for drug delivery have also been met with little success.
Nucleic acid delivery from coatings have also been problematic in that the ability to transfer nucleic acid efficiently into a targeted cell population and achieve a high level of expression of the gene product in vivo is limited. Incorporating plasmid DNA into a collagen sponge and implanting it in bone can successfully deliver the nucleic acid, but most of the DNA escapes in a very short time (less than one hour). Bonadio et al., Nat. Med. 1999, 5(7):753-9. In principle, therefore, larger amounts of nucleic acid would be required for adequate delivery. Id. Various DNA delivery systems have been employed to localize and sustain gene transfer activity in this context, with mixed results.